Liver Damage in Acute Heliotrine Poisoning 2. THE EFFECT OF NICOTINAMIDE ON PYRIDINE NUCLEOTIDE

Earlier studies on the effects of heliotrine poisoning demonstrated an apparent deficiency of DPN in homogenate and mitochondrial preparations from the livers of heliotrine-poisoned (1620hr.) rats (Christie, 1958b). More recent work has shown that the concentrations of pyridine nucleotides were, in fact, decreased in homogenates and in the mitochondrial and soluble fractions of liver from rats treated with heliotrine for 17-20 hr. (Christie, Le Page & Bailie, 1961; Christie & Le Page, 1962). From these studies it was proposed that much of the decrease in the concentrations of pyridine nucleotides in vivo came about by passage of coenzymes out of liver cells when they were, as yet, only moderately damaged. Further losses could have occurred when cells were eventually disrupted, and some losses of nucleotide may have occurred from breakdown by enzymes such as pyridine nucleotidases. It was also suggested that heliotrine might reduce the capacity of the liver to synthesize pyridine nucleotides: thus the ability of the liver to maintain normal concentrations in the presence of increased losses would be decreased (Christie & Le Page, 1962). In this paper we describe studies of the capacity of the heliotrine-poisoned-rat liver to synthesize pyridine nucleotide coenzymes in vivo. Nicotinamide administration to normal mice was shown by Kaplan, Goldin, Humphreys, Ciotti & Stolzenbach (1956b) to lead to a marked elevation of the total pyridine coenzyme concentration of the liver, The increase was largely accounted for by a tenfold increase in the DPN concentration. Further, the newly synthesized DPN was nearly all in the soluble fraction of mouse liver; there was no significant rise in the concentration of TPN (Kaplan et al. 1956b). Nicotinic acid, on the other hand, although favoured as a direct precursor of DPN (Preiss & Handler, 1957, 1958a, b), when administered in equivalent dosage, gave only a relatively small increase in DPN (Kaplan et al. 1956b; Kaplan, Goldin, Humphreys & Stolzenbach, 1957; Kaplan, 1960). In view of these findings it is apparent that one possible way of testing whether heliotrine interferes with DPN synthesis in rat liver in vivo would * Part 1: Christie & Le Page (1962). be to study the 'response' to injections of nicotinamide shown by rats treated with heliotrine. Our experiments show that the ability to 'respond' to nicotinamide injections is reduced with increasing duration of heliotrine treatment.